DRUGS

1. DRUGS AN INTRODUCTION

2. WHY STUDY DRUGS?

3. WHY STUDY DRUGS?

4. WHY STUDY DRUGS?

5. WHAT IS A DRUG? A drug is any absorbed or applied substance that induces a biological response in the body. It can be taken via oral methods, intravenously or simply applied directly onto the skin.

6. WHAT ARE THE EFFECTS? As mentioned, drugs can induce biological responses in the body. These responses can include primary effects that are beneficial and therapeutic. However, side effects may also occur, and they can be potentially lethal.

7. CASE STUDY OF MORPHINE Morphine is an analgesic, or a painkiller, that stimulates the production of endorphins and enkephalins in our body, which helps to ease the pain. However, side effects include addiction and over-dependence. So, under what circumstances should we prescribe morphine?

8. A LOOK AT THALIDOMIDE Thalidomide was meant as a sedative and hypnotic drug. However, what the scientists did not realise was that it had 2 enantiomers. Enantiomers are isomers with non-superimposable arrangements of atoms in space.

9. A LOOK AT THALIDOMIDE The R-isomer was therapeutically effective, but the S-isomer was teratogenic, and it caused numerous birth defects. Patients were prescribed racemic mixtures, meaning it contained equal amounts of both isomers.

10. AN IDEAL DRUG Low toxicity Ensures that it is safe for consumption and few side effects High selectivity Kills only the cells you want it to kill! High chemical stability Ensures durability For example, penicillin can be hydrolysed by acid. Hence, side groups have to be modified such that it is acid-resistant. High purity

11. HOW DOES A DRUG WORK? A drug works based on the receptor theory, which states that the drug molecule bind to a receptor molecule in the body, eliciting a biological response.

12. HOW DOES A DRUG WORK? Drugs can bind to the receptor via various intermolecular forces. Ion-dipole interactions Hydrogen bonding Ionic attractions Covalent bonding Van der Waals� forces

13. HOW DOES A DRUG WORK?

14. AGONISTS AND ANTAGONISTS Drugs, when bound to receptors, can be agonists or antagonists. Agonists activate receptors and elicit the maximum physiological response. Antagonists merely occupy the receptor site and block the natural substrate from binding to the receptor, hence preventing any cellular response.

15. AGONISTS

16. ANTAGONISTS

17. ENZYME INHIBITION Common receptors include proteins and enzymes. Why? To stop the illness, we can inhibit the action of the enzyme. For example, azidothymidine inhibits the action of HIV reverse transcriptase, hence stopping the virus from multiplying. Inhibition can be competitive or non-competitive.

18. ENZYME INHIBITION

19. DRUG DISCOVERY

20. DRUG DISCOVERY

21. DRUG DISCOVERY

22. DRUG DISCOVERY

23. TARGET IDENTIFICATION ????,???? Knowledge of the pathogen and its biochemistry would have to stem from knowledge of molecular biology. For example, a medicinal chemist would need to know how HIV proliferates and what enzymes are required before he decide on the target. The target, in this case, can be HIV protease, which synthesizes proteins for new viruses.

24. TARGET IDENTIFICATION

25. LEAD IDENTIFICATI0N The drug/groups of atoms that are potentially beneficial have to be identified. This is known as the pharmacophore. This can be done through in vitro AND in vivo tests. In vitro---tests in external environment In vivo---tests carried out in body environment

26. LEAD IDENTIFICATION

27. LEAD IDENTIFICATION

28. LEAD IDENTIFICATION

29. LEAD OPTIMIZATION The lead needs to be chemically modified to make it optimum for operation in the body. For example, side groups of penicillin need to be modified to make it resistant to acid in the stomach. Chemists hence need to modify side groups without losing the pharmacophore. How do they decide whether the drug is optimum?

30. ADME CRITERIA Chemists base their judgments on the following criteria: Absorption Distribution Metabolism Excretion For penicillin to be acid-resistant, the chemistry of it must be understood. (trick is to make the side groups electron- withdrawing such that N atom cannot attack the carbonyl group)

31. CLINICAL TRIALS Preclinical trials carried out on animals (vivisection). Ethical issues very much involved. Clinical trials carried out on humans. Placebo effect is an obstacle.

32. PLACEBO EFFECT Refers to a measurable and observable effect not directly caused by the drug itself. To overcome this, a double blind study must be carried out. Neither the doctor nor the patient knows which is the real deal or the placebo. Only the experimenter knows�haha�

33. SUMMARY Drug testing involves: Target identification Lead identification Lead optimization Clinical trials (phase I, II, III and IV) Would drugs that pass all 4 stages necessarily be safe?

34. ANTIBIOTICS--PENICILLIN Penicillin is a drug derived from the fungi of Penicillum chrysogenum, serendipitously discovered by Sir Alexander Fleming and his blundering assistant.

35. HYDROLYSIS OF PENICILLIN Penicillin can be hydrolysed by nucleophilic acyl substitution. Nucleophile = �nucleus-loving�, negative species which usually contain a lone pair of electrons in non-bonding orbitals Nucleophile attacks carbon atom of carbonyl group, as carbon atom is a region of low electron density. Why?

36. HYDROLYSIS OF PENICILLIN

37. HYDROLYSIS OF PENICILLIN

38. HYDROLYSIS OF PENICILLIN Usually takes place in acid medium of stomach, since protonation can increase chance of nucleophilic attack. (look up exact mechanism in Organic Chemistry by Wade) Nucleophile approaches carbonyl group at 107 degrees: Burgi Dunitz Trajectory.

39. HOW DOES IT WORK? Pencillin is a competitive inhibitor of transpeptidase, which catalyses the formation of cross-linkages between sugar backbones to form bacterial cell walls.

40. HOW DOES IT WORK? B-lactam ring is structurally similar to natural substrate D-Ala-D-Ala. (recall competitive inhibition)

41. HOW DOES IT WORK? By inhibiting cell wall synthesis, the bacterial cell lyses. Penicillin is only effective for Gram-positive bacteria that have a thicker layer of peptidoglycan cell wall. It is unable to penetrate the lipoprotein envelope of Gram-negative bacteria.

43. WHY SO MANY TYPES? Part of lead optimization For higher durability Methicillin is B-lactamase resistant and can hence last longer without being degraded. For easier absorption Amoxicillin is acid resistant and can ingested easily. For therapeutic effectiveness Only penicillin G is effective out of penicillins X, F, G and K.

44. THE FUTURE� Computer aided drug design Rational drug design De novo drug design Nanoscience---specific drug delivery Gene therapy Possible cures for cancer?

45. COMPUTER AIDED DRUG DESIGN

46. RATIONAL DRUG DESIGN

47. De novo drug design

48. Nanoscience

49. GENE THERAPY AND CANCER